Genome-Wide Association Study of Childhood Leukemia by Hispanic Status

按西班牙裔身份划分的儿童白血病全基因组关联研究

• 批准号: 8026191
• 负责人: Xiaomei Ma
• 金额: $ 156.61万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8026191
• 关键词: Accounting; Acute Lymphocytic Leukemia; African American; Algorithms; Alleles; American; Archives; Birth; Birth Order; Birth Records; Birth Weight; Blood; California; Case-Control Studies; Characteristics; Child; Childhood Acute Lymphocytic Leukemia; Childhood Leukemia; Coupled; Custom; Data; Development; Dimensions; Disease; Dose; Down Syndrome; Ensure; Ethnic Origin; Ethnic group; Etiology; European; Exposure to; Fetal Growth; Funding; Gender; Genes; Genetic Predisposition to Disease; Genetic Risk; Genome; Genomics; Genotype; Gestational Age; Goals; Growth; Hereditary Disease; Hispanics; Incidence; Infant; Ionizing radiation; Link; Malignant Neoplasms; Measures; Meta-Analysis; Neonatal; Not Hispanic or Latino; Odds Ratio; Only Child; Parental Ages; Phase; Population; Population Study; Pregnancy; Process; Public Health; Publishing; Race; Reporting; Research; Risk; Risk Factors; Role; Sample Size; Sampling; Screening procedure; Single Nucleotide Polymorphism; Spottings; Time; United States; United States National Institutes of Health; Validation; Vulnerable Populations; base; case control; design; ethnic difference; genetic risk factor; genetic variant; genome wide association study; improved; in utero; leukemia; leukemogenesis; neoplasm registry; parity; population based; programs; response

DESCRIPTION (provided by applicant): Although acute lymphoblastic leukemia (ALL) is the most common malignancy in children (0 - 14 years), there are few known risk factors. In the United States, Hispanic children have higher incidence of ALL than any other ethnic/racial groups; they have 1.3 times of the risk for ALL than non-Hispanic white children. Two small genome-wide association studies (GWAS) recently identified 2-3 genetic risk factors for childhood ALL, but only in European white populations with non-population based ascertainment. High birth weight and other markers of fetal growth have been consistently linked to an increased risk of childhood ALL in most studies, and Hispanics appear to have accelerated fetal growth early on during pregnancy. In the current application, we seek to significantly advance leukemia research by clarifying the roles of genetic susceptibility and fetal growth in the etiology of childhood ALL in a large population-based sample of Hispanics and non-Hispanic whites in California, using high dimension arrays specifically designed for the two ethnic groups. We will (1) link California birth records with California Cancer Registry data (1988 - 2008) to assemble a population-based case-control study with an unprecedented size (4,000 cases and 4,000 controls, about half of which will be Hispanics and half non-Hispanic whites); (2) obtain the archived neonatal dried blood spots of all cases and controls from the California Department of Public Health; (3) genotype the study population with custom Affymetrix whole genome arrays designed for the California population, with optimized designs for Hispanics and non-Hispanic whites separately; (4) use data from these cases and controls to identify distinct and shared genetic risk alleles for Hispanics and non-Hispanic whites; and (5) validate top GWAS hits in the California Childhood Leukemia Study (an ongoing NIH-funded case-control study with a separate and distinct subject ascertainment, >1000 cases, > 1000 controls, approximately half of which will be Hispanics and half non- Hispanic whites) and in a Brazilian childhood leukemia study with Latin American cases (n = 200) and controls (n = 400). In addition, we will utilize data on the characteristics of all births in California during 1988 - 2008 to develop an algorithm to predict birth weight based on factors such as gestational age, gender, birth order, parental race, parental Hispanic status, and parental ages, and calculate a proportion of expected birth weight (PEBW) for all cases and controls (n = 8000) by dividing their actual observed birth weight by the expected birth weight derived from the algorithm. Subsequently, we will determine whether the PEBW or birth weight is associated with (i) childhood ALL, (ii) the top GWAS hits, and (iii) the SNPs in genes potentially related to fetal growth, in Hispanics and non-Hispanic whites separately. Given the unprecedented sample size, especially the large number of Hispanics included, and ethnic-specific genotyping panels with great genome coverage, this study will clarify the role of genetic susceptibility in childhood ALL, the mechanism involving fetal growth, and in the process identify potential reasons for the puzzling ethnic difference in disease incidence. PUBLIC HEALTH RELEVANCE: We do not yet understand the causes of childhood leukemia. The goal of this project is to discover genetic risk factors for childhood acute lymphoblastic leukemia, and examine the relationship between these genetic risk and fetal growth variables in leukemia incidence. We will explore the impact of these variables on Hispanics and Whites in California to investigate why Hispanics have a higher rate of leukemia, significantly improving our understanding of the causes of this disease in the most vulnerable populations.

描述（由申请人提供）：虽然急性淋巴细胞白血病（ALL）是儿童（0 - 14岁）中最常见的恶性肿瘤，但已知的风险因素很少。在美国，西班牙裔儿童的ALL发病率高于任何其他种族/人种;他们的ALL风险是非西班牙裔白色儿童的1.3倍。两个小的全基因组关联研究（GWAS）最近确定了2-3个儿童ALL的遗传风险因素，但仅在欧洲白色人群中进行了非人群基础的确定。在大多数研究中，高出生体重和其他胎儿生长标志物一直与儿童ALL风险增加有关，西班牙裔似乎在怀孕早期加速了胎儿生长。在本申请中，我们寻求通过使用专门为两个种族群体设计的高维阵列，在加州的西班牙裔和非西班牙裔白人的大的基于人群的样本中阐明遗传易感性和胎儿生长在儿童ALL的病因学中的作用来显著推进白血病研究。我们将（1）将加州出生记录与加州癌症登记数据相关联（1988 - 2008），以前所未有的规模进行基于人群的病例对照研究（4,000例病例和4,000例对照，其中大约一半是西班牙裔，一半是非西班牙裔白人）;（2）从加州公共卫生部获得所有病例和对照的存档新生儿干血斑;（3）用为加州人群设计的定制Affyellow全基因组阵列对研究人群进行基因分型，分别为西班牙裔和非西班牙裔白人进行优化设计;（4）使用这些病例和对照的数据来识别西班牙裔和非西班牙裔白人的不同和共享的遗传风险等位基因;和（5）验证加州儿童白血病研究中的顶级GWAS命中（一项正在进行的NIH资助的病例对照研究，具有单独和不同的受试者确定，>1000例，> 1000对照，其中大约一半是西班牙裔和一半非西班牙裔白人）和巴西儿童白血病研究中的拉丁美洲病例（n = 200）和对照（n = 400）。此外，我们将利用1988 - 2008年期间加州所有出生特征的数据，开发一种算法，根据胎龄、性别、出生顺序、父母种族、父母西班牙裔身份和父母年龄等因素预测出生体重，并通过将所有病例和对照组（n = 8000）的实际观察到的出生体重除以从该算法得出的预期出生体重来计算预期出生体重（PEBW）的比例。随后，我们将分别在西班牙裔和非西班牙裔白人中确定PEBW或出生体重是否与（i）儿童期ALL，（ii）最高GWAS命中率和（iii）可能与胎儿生长相关的基因中的SNP相关。鉴于前所未有的样本量，特别是大量的西班牙裔，和种族特异性基因分型面板与巨大的基因组覆盖率，这项研究将阐明遗传易感性在儿童ALL中的作用，涉及胎儿生长的机制，并在此过程中确定疾病发病率令人困惑的种族差异的潜在原因。 公共卫生相关性：我们还不了解儿童白血病的原因。本项目的目的是发现儿童急性淋巴细胞白血病的遗传危险因素，并检查这些遗传危险因素与白血病发病率中胎儿生长变量之间的关系。我们将探讨这些变量对加州西班牙裔和白人的影响，以调查为什么西班牙裔有更高的白血病发病率，显着提高我们对这种疾病的原因在最脆弱的人群的理解。